Up-regulation of mismatch repair genes MSH6, PMS2 and MLH1 parallels development of genetic instability, and is linked to tumor aggressiveness and early PSA recurrence in prostate cancer

DNA mismatch repair (MMR) is integral to the maintenance of genetic stability. We aimed to evaluate the clinical impact of MMR gene expression in prostate cancer. The MMR genes MSH6, MLH1 and PMS2 were analyzed by immunohistochemistry on a tissue microarray containing 11 152 prostate cancer specimens. Results were compared with ERG status and deletions of PTEN, 3p13, 5q21, and 6q15. MSH6, MLH1 and PMS2 expression was detectable in 89.5%, 85.4% and 85.0% of cancers, and was particularly strong in cancers with advanced pathological tumor stage (p<0.0001 each), high Gleason grade (p<0.0001 each), nodal metastasis (p≤0.0083), and early biochemical recurrence (p<0.0001). High levels of MMR gene expression paralleled features of genetic instability, such as the number of genomic deletions per cancer; strong expression of all three MMR genes was found in 24%, 29%, 30%, 33% and 42% of cancers with no, one, two, three or four to five deletions (p<0.0001). The prognostic value of the analyzed MMR genes was largely driven by the subset of cancers lacking ERG-fusion (p<0.0001), while the prognostic impact of MMR gene overexpression was only marginal in ERG-positive cancers. Multivariate analyses suggested an independent prognostic relevance of MMR genes in ERG-negative prostate cancers when compared to prognostic parameters available at the time of initial biopsy. In conclusion, MMR overexpression is common in prostate cancer, and is linked to poor outcome as well as features indicating genetic instability. ERG-fusion should be analyzed along with MMR gene expression in potential clinical tests.

Carcinogenesis. 2016 Nov 01 [Epub ahead of print]

Waldemar Wilczak, Semin Rashed, Claudia Hube-Magg, Martina Kluth, Ronald Simon, Franziska B├╝scheck, Till Sebastian Clauditz, Katharina Grupp, Sarah Minner, Maria Christina Tsourlakis, Christina Koop, Markus Graefen, Meike Adam, Alexander Haese, Corinna Wittmer, Guido Sauter, Jakob Robert Izbicki, Hartwig Huland, Thorsten Schlomm, Stefan Steurer, Till Krech, Patrick Lebok

Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany., Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany ., General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Germany., Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Germany.